The development of non-opioid analgesics for the control of postsurgical pain is widely acknowledged as an important goal. The side effects of opioids, most notably respiratory depression, but also including sedation, nausea, constipation, and sleep impairment make their use challenging and even potentially life-threatening. Of course, the difficulties posed by opioid use are magnified tremendously by the potential for addiction and abuse. In large part because of the need to limit the use of opioids, the moderate, severe, or extreme pain experienced by about 80% of patients after surgery is often undertreated. Adjuvant agents such as gabapentin, magnesium, and ketamine are used in the perioperative setting (multimodal therapy) to reduce acute postoperative pain and the development of persistent pain, as well as to reduce use of opioids. Unfortunately however, many of the most efficacious add on therapies also carry negative side effects related to the central nervous system (CNS). There remains a need for new classes of potent and effective analgesics for treatment of postoperative pain that do not have CNS-related side effects and high abuse potential. We believe that metabolically stable, peripherally-restricted galanin analogs have the potential to replace or reduce the use of opioids in treatment of acute postoperative pain. However, there is confusion in literature about the galanin receptor subtype that would be more effective in mediating antinociception. We will evaluate two analogs in this proposal, with the goal of selecting a lead candidate for phase 2 efforts focused on drug development activities. One of these analogs is somewhat selective for the galanin type 1 receptor, the other being somewhat galanin type 2 receptor preferring. Both have shown good efficacy in various rodent models of pain and no evidence of major side effects like those associated with opioids. In this phase 1 application, we will evaluate our two analogs in mice to determine pharmacokinetic (PK) parameters, potency and efficacy in the plantar incision model of postsurgical pain, and toxicity over the course of a 7-day study. Completion of these aims will allow us to better define the PK, efficacy, and short-term toxicity of our two analogs, allowing us to select one compound as the lead for subsequent phase 2 studies. This phase 1 project is the starting point for exploring the efficacy of galanin analogs for multiple pain states; information gained in this project will supplement efforts to develop a galanin analog for other forms of pain beyond postoperative. Metabolically stable, peripherally restricted galanin analogs represent novel, first-in- class pharmacologic therapies to replace or reduce use of opioids and other CNS-active therapies in treatment of postoperative pain.